EFHD2 regulates T cell receptor signaling and modulates T helper cell activation in early sepsis.

EFHD2 (EF-hand domain family, member D2) has been identified as a calcium-binding protein with immunomodulatory effects. In this study, we characterized the phenotype of Efhd2-deficient mice in sepsis and examined the biological functions of EFHD2 in peripheral T cell activation and T helper (Th) cell differentiation. Increased levels of EFHD2 expression accompanied peripheral CD4+ T cell activation in the early stages of sepsis. Transcriptomic analysis indicated that immune response activation was impaired in Efhd2-deficient CD4+ T cells. Further, Efhd2-deficient CD4+ T cells isolated from the spleen of septic mice showed impaired T cell receptor (TCR)-induced Th differentiation, especially Th1 and Th17 differentiation. In vitro data also showed that Efhd2-deficient CD4+ T cells exhibit impaired Th1 and Th17 differentiation. In the CD4+ T cells and macrophages co-culture model for antigen presentation, the deficiency of Efhd2 in CD4+ T cells resulted in impaired formation of immunological synapses. In addition, Efhd2-deficient CD4+ T cells exhibited reduced levels of phospho-LCK and phospho-ZAP70, and downstream transcription factors including Nfat, Nfκb and Nur77 following TCR engagement. In summary, EFHD2 may promote TCR-mediated T cell activation subsequent Th1 and Th17 differentiation in the early stages of sepsis by regulating the intensity of TCR complex formation.

Glymphatic System Dysfunction Underlying Schizophrenia Is Associated With Cognitive Impairment.

BACKGROUND AND HYPOTHESIS: Despite the well-documented structural and functional brain changes in schizophrenia, the potential role of glymphatic dysfunction remains largely unexplored. This study investigates the glymphatic system's function in schizophrenia, utilizing diffusion tensor imaging (DTI) to analyze water diffusion along the perivascular space (ALPS), and examines its correlation with clinical symptoms. STUDY DESIGN: A cohort consisting of 43 people with schizophrenia and 108 healthy controls was examined. We quantified water diffusion metrics along the x-, y-, and z-axis in both projection and association fibers to derive the DTI-ALPS index, a proxy for glymphatic activity. The differences in the ALPS index between groups were analyzed using a 2-way ANCOVA controlling for age and sex, while partial correlations assessed the association between the ALPS index and clinical variables. STUDY RESULTS: People with schizophrenia showed a significantly reduced DTI-ALPS index across the whole brain and within both hemispheres (F = 9.001, P = .011; F = 10.024, P = .011; F = 5.927, P = .044; false discovery rate corrected), indicating potential glymphatic dysfunction in schizophrenia. The group by cognitive performance interaction effects on the ALPS index were not observed. Moreover, a lower ALPS index was associated with poorer cognitive performance on specific neuropsychological tests in people with schizophrenia. CONCLUSION: Our study highlights a lower ALPS index in schizophrenia, correlated with more pronounced cognitive impairments. This suggests that glymphatic dysfunction may contribute to the pathophysiology of schizophrenia, offering new insights into its underlying mechanisms.

Microascaceae from the Marine Environment, with Descriptions of Six New Species.

Most reported members of Microascaceae that have been reported originate from the terrestrial environment, where they act as saprobes or plant pathogens. However, our understanding of their species diversity and distribution in the marine environment remains vastly limited, with only 22 species in nine genera having been reported so far. A survey of the fungal diversity in intertidal areas of China's mainland has revealed the discovery of several Microascaceae strains from 14 marine algae and 15 sediment samples. Based on morphological characteristics and LSU-ITS-tef1-tub2 multilocus phylogeny using Bayesian inference and maximum likelihood methods, 48 strains were identified as 18 species belonging to six genera. Among these, six new species were discovered: Gamsia sedimenticola, Microascus algicola, M. gennadii, Scedosporium ellipsosporium, S. shenzhenensis, and S. sphaerospermum. Additionally, the worldwide distribution of the species within this family across various marine habitats was briefly reviewed and discussed. Our study expands the knowledge of species diversity and distribution of Microascaceae in the marine environment.

Cortical changes in the brain of patients with hemifacial spasm.

OBJECTIVE: Hemifacial spasm (HFS) is a movement disorder characterized by involuntary muscle contractions on one side of the face. It is associated with disturbances in the brain's functional architecture. Despite this, the structural alterations in the brain related to HFS remain poorly understood. In this study, we investigated the cortical morphology changes in patients with HFS compared to healthy controls (HCs). METHODS: We analyzed 3D T1-weighted MRI images from 33 patients with left-sided primary HFS and 33 age- and sex-matched HCs. Measurements of cortical thickness (CTh), sulcal depth, local gyrification index (lGI), and fractal dimension were taken using a computational anatomy toolbox. A general linear model, accounting for age, gender, and total brain volume, was applied for statistical analyses. Significant clusters were then assessed for correlations with clinical parameters. RESULTS: The HFS patients displayed several cortical abnormalities when compared to HCs, including reduced CTh in the contralateral precentral gyrus and left orbitofrontal cortex, decreased sulcal depth in the left orbitofrontal cortex, and increased lGI in the right insula and superior temporal cortex. However, fractal dimension did not differ significantly between the groups. Additionally, in HFS patients, a notable negative correlation was found between the sulcal depth in the left orbitofrontal cortex and the Beck Depression Inventory-II scores. CONCLUSIONS: Our findings reveal that HFS is associated with specific surface-based morphological changes in the brain. These alterations contribute to a deeper understanding of the neurophysiological mechanisms involved in HFS and may have implications for future research and treatment strategies.

Progressive white matter degeneration in patients with spinocerebellar ataxia type 2.

PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder characterized by cerebellar atrophy. However, studies to elucidate the longitudinal progression of the neuropathology are limited. We sought to identify brain macrostructural and microstructural alterations in patients with SCA2 using fixel-based analysis (FBA) to better understand its distribution patterns and progression. METHODS: We enrolled 9 patients with SCA2 and 16 age- and gender-matched controls. Longitudinal clinical and imaging data were collected at baseline, and 3.5 years later. Fiber density (FD), fiber-bundle cross-section (FC), and a combination of FD and FC (FDC) were calculated. The paired t-test was used to examine longitudinal differences. The associations between fixel-based metrics and clinical variables were explored in SCA2 patients. RESULTS: At baseline, patients with SCA2 displayed multiple white matter tracts with significantly decreased FD, FC, and FDC in the corticospinal tract, cerebellar peduncles, brainstem, corpus callosum, thalamus, striatum, and prefrontal cortex, compared to controls. Over time, many of these macrostructural and microstructural alterations progressed, manifesting lower FD, FC, and FDC in corticospinal tract, middle cerebellar peduncle, brainstem, striatum, fornix, and cingulum. No significant brain white matter alterations were found in the healthy controls over time. There was no association between the FBA-derived metrics and clinical variables in SCA2. CONCLUSION: This study provides evidence of brain macrostructural and microstructural alterations and of progression over time in SCA2. The FBA-derived metrics may serve as potential biomarkers of SCA2 progression.

Topological alterations in white matter structural networks in fibromyalgia.

PURPOSE: Neuroimaging studies employing analyses dependent on regional assumptions and specific neuronal circuits could miss characteristics of whole-brain structural connectivity critical to the pathophysiology of fibromyalgia (FM). This study applied the whole-brain graph-theoretical approach to identify whole-brain structural connectivity disturbances in FM. METHODS: This cross-sectional study used probabilistic diffusion tractography and graph theory analysis to evaluate the topological organization of brain white matter networks in 20 patients with FM and 20 healthy controls (HCs). The relationship between brain network metrics and clinical variables was evaluated. RESULTS: Compared with HCs, FM patients had lower clustering coefficient, local efficiency, hierarchy, synchronization, and higher normalized characteristic path length. Regionally, patients demonstrated a significant reduction in nodal efficiency and centrality; these regions were mainly located in the prefrontal, temporal cortex, and basal ganglia. The network-based statistical analysis (NBS) identified decreased structural connectivity in a subnetwork of prefrontal cortex, basal ganglia, and thalamus in FM. There was no correlation between network metrics and clinical variables (false discovery rate corrected). CONCLUSIONS: The current research demonstrated disrupted topological architecture of white matter networks in FM. Our results suggested compromised neural integration and segregation and reduced structural connectivity in FM.

Decreased DTI-ALPS and choroid plexus enlargement in fibromyalgia: a preliminary multimodal MRI study.

PURPOSE: The glymphatic system is a fluid exchange pathway that clears waste products that is crucial for the maintenance of brain homeostasis. However, the exact role it plays in the emergence of fibromyalgia (FM) is still not fully understood. Here, we explored the changes in non-invasive MRI proxy probably related to the glymphatic function in FM patients, and explored brain-behavior relationships. METHODS: A total of 40 participants, consisting of 20 individuals with FM and 20 healthy controls (HCs), were included in the study. The participants underwent structural T1-weighted MRI, diffusion tensor imaging (DTI), and clinical assessment. The data was obtained from an open access dataset. The study compared non-invasive MRI indices, including choroid plexus (CP) volume and DTI analysis along the perivascular space (ALPS), between the FM and HC groups. Furthermore, correlation analysis was conducted to determine the correlation between clinical parameters and both CP volume and DTI-ALPS index. RESULTS: Patients with FM had significantly higher CP volume and a lower DTI-ALPS index than HCs adjusting for age and intracranial volume. Higher CP volume was associated with lower DTI-ALPS index, and longer disease duration. CONCLUSION: Our findings demonstrate aberrant glymphatic function in FM, and that dysfunction in the brain glymphatic system may play a role in the neural mechanisms underlying FM.

Efficacy and safety of selenium or vitamin E administration alone or in combination in ICU patients: A systematic review and meta-analysis.

BACKGROUND: Micronutrient administration that contributes to antioxidant defense has been extensively studied in critically ill patients, but consensus remains elusive. Selenium and vitamin E are two important micronutrients that have synergistic antioxidant effects. This meta-analysis aimed to assess the effect of selenium or vitamin E administration alone and the combination of both on clinical outcomes in patients hospitalized in the ICU. METHODS: After electronic searches on PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), SinoMed, VIP database and Wanfang data, initially 1767 papers were found, and 30 interventional studies were included in this analysis. We assessed the risk-difference between treatment and control (standard treatment) groups by pooling available data on length of stay (ICU length of stay and hospital length of stay), mortality (ICU mortality, hospital mortality, 28-day mortality, 6-month mortality and all-cause mortality), duration of mechanical ventilation, adverse events and new infections. RESULTS: By analyzing the included studies, we found no significant effect of selenium administration alone on mortality, mechanical ventilation duration, or adverse events in ICU patients. However, after excluding studies with high heterogeneity, the meta-analysis showed that selenium alone reduced the length of hospital stay (MD: -1.38; 95% CI: -2.52, -0.23; I-square: 0%). Vitamin E administration alone had no significant effect on mortality, duration of mechanical ventilation, or adverse events in ICU patients. However, after excluding studies with high heterogeneity, the meta-analysis showed that vitamin E alone could reduce the length of ICU stay (MD: -1.27; 95% CI: -1.86, -0.67; I-square: 16%). Combined administration of selenium and vitamin E had no significant effect on primary outcomes in ICU patients. CONCLUSIONS: Selenium administration alone may shorten the length of hospital stay, while vitamin E alone may reduce the length of ICU stay. The putative synergistic beneficial effect of combined administration of selenium and vitamin E in ICU patients has not been observed, but more clinical studies are pending to confirm it further.

Clinical characterization of EFHD2 (swiprosin-1) in Glioma-associated macrophages and its role in regulation of immunosuppression.

Glioblastoma has been extensively studied due to its high mortality and short survival. The evolution mechanism of tumor-associated macrophages (TAMs) to Glioma-associated microglia and macrophages (GAMs) in the tumor microenvironment (TME) remains to be elucidated. The tumor cell-to-cell interaction patterns have not been well defined yet. The EF-Hand Domain Family Member D2 (EFHD2) has been reported to be differentially expressed as an immunomodulatory molecule in a variety of cancers. But large-scale clinical data from multiple ethnic communities have not been used to investigate the role of EFHD2 in glioma. RNA-seq data from 313 or 657 glioma patients from the Chinese Glioma Genome Atlas (CGGA) database and 603 glioma patients from the Cancer Genome Atlas (TCGA) database were analyzed retrospectively. Cell localization was performed using single-cell sequencing data from the CGGA database and the GSE131928 dataset. Mouse glioma cell lines and primary macrophages isolated from Efhd2 knockout mice were co-cultured to validate the immunomodulatory effects of EFHD2 on macrophages and the remodeling of TME of glioblastoma. EFHD2 is enriched in high-grade gliomas, isocitrate dehydrogenase wild-type, and 1p/19q non-co-deficient gliomas. It is a potential biomarker of glioma-proneuronal subtypes and an independent prognostic factor for overall survival in patients with malignant glioblastoma. EFHD2 regulates the monocyte-macrophage system function and positively correlates with immunosuppressive checkpoints. Further experimental data demonstrates that Efhd2 influences the polarization state of GAMs and inhibits the secretion of TGF-ß1. In vitro experiments have revealed that macrophages lacking Efhd2 suppress the vitality of two glioma cell lines and decelerate the growth of glioma xenografts. In conclusion, EFHD2 promises to be a key target for TME-related immunotherapy.

Corrigendum: Curcumin alleviates experimental colitis in mice by suppressing necroptosis of intestinal epithelial cells.

[This corrects the article DOI: 10.3389/fphar.2023.1170637.].

The Dopaminergic System in the Ventral Tegmental Area Contributes to Morphine Analgesia and Tolerance.

Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which limits its clinical application. The complex mechanisms underlying the development of morphine analgesia into tolerance involve multiple nuclei in the brain. Recent studies reveal the signaling at the cellular and molecular levels as well as neural circuits contributing to morphine analgesia and tolerance in the ventral tegmental area (VTA), which is traditionally considered a critical center of opioid reward and addiction. Existing studies show that dopamine receptors and µ-opioid receptors participate in morphine tolerance through the altered activities of dopaminergic and/or non-dopaminergic neurons in the VTA. Several neural circuits related to the VTA are also involved in the regulation of morphine analgesia and the development of drug tolerance. Reviewing specific cellular and molecular targets and related neural circuits may provide novel precautionary strategies for morphine tolerance.

Programmed death of intestinal epithelial cells in neonatal necrotizing enterocolitis: a mini-review.

Necrotizing enterocolitis (NEC) is one of the most fatal diseases in premature infants. Damage to the intestinal epithelial barrier (IEB) is an important event in the development of intestinal inflammation and the evolution of NEC. The intestinal epithelial monolayer formed by the tight arrangement of intestinal epithelial cells (IECs) constitutes the functional IEB between the organism and the extra-intestinal environment. Programmed death and regenerative repair of IECs are important physiological processes to maintain the integrity of IEB function in response to microbial invasion. However, excessive programmed death of IECs leads to increased intestinal permeability and IEB dysfunction. Therefore, one of the most fundamental questions in the field of NEC research is to reveal the pathological death process of IECs, which is essential to clarify the pathogenesis of NEC. This review focuses on the currently known death modes of IECs in NEC mainly including apoptosis, necroptosis, pyroptosis, ferroptosis, and abnormal autophagy. Furthermore, we elaborate on the prospect of targeting IECs death as a treatment for NEC based on exciting animal and clinical studies.

Mapping the human oral and gut fungal microbiota in patients with metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a phenotype of liver diseases associated with metabolic syndrome. The pathogenesis MAFLD remains unclear. The liver maintains is located near the intestine and is physiologically interdependent with the intestine via metabolic exchange and microbial transmission, underpinning the recently proposed "oral-gut-liver axis" concept. However, little is known about the roles of commensal fungi in the disease development. This study aimed to characterize the alterations of oral and gut mycobiota and their roles in MAFLD. Twenty-one MAFLD participants and 20 healthy controls were enrolled. Metagenomics analyses of saliva, supragingival plaques, and feces revealed significant alterations in the gut fungal composition of MAFLD patients. Although no statistical difference was evident in the oral mycobiome diversity within MAFLD and healthy group, significantly decreased diversities were observed in fecal samples of MAFLD patients. The relative abundance of one salivary species, five supragingival species, and seven fecal species was significantly altered in MAFLD patients. Twenty-two salivary, 23 supragingival, and 22 fecal species were associated with clinical parameters. Concerning the different functions of fungal species, pathways involved in metabolic pathways, biosynthesis of secondary metabolites, microbial metabolism in diverse environments, and carbon metabolism were abundant both in the oral and gut mycobiomes. Moreover, different fungal contributions in core functions were observed between MAFLD patients and the healthy controls, especially in the supragingival plaque and fecal samples. Finally, correlation analysis between oral/gut mycobiome and clinical parameters identified correlations of certain fungal species in both oral and gut niches. Particularly, Mucor ambiguus, which was abundant both in saliva and feces, was positively correlated with body mass index, total cholesterol, low-density lipoprotein, alanine aminotransferase, and aspartate aminotransferase, providing evidence of a possible "oral-gut-liver" axis. The findings illustrate the potential correlation between core mycobiome and the development of MAFLD and could propose potential therapeutic strategies.

The associations of gut microbiota, endocrine system and bone metabolism.

Gut microbiota is of great importance in human health, and its roles in the maintenance of skeletal homeostasis have long been recognized as the "gut-bone axis." Recent evidence has indicated intercorrelations between gut microbiota, endocrine system and bone metabolism. This review article discussed the complex interactions between gut microbiota and bone metabolism-related hormones, including sex steroids, insulin-like growth factors, 5-hydroxytryptamine, parathyroid hormone, glucagon-like peptides, peptide YY, etc. Although the underlying mechanisms still need further investigation, the regulatory effect of gut microbiota on bone health via interplaying with endocrine system may provide a new paradigm for the better management of musculoskeletal disorders.

Curcumin alleviates experimental colitis in mice by suppressing necroptosis of intestinal epithelial cells.

Curcumin, the primary bioactive substance in turmeric, exhibits potential therapeutic effects on ulcerative colitis. However, its mechanism for regulating necroptosis in colitis has not been fully elucidated. In this study, the effect of curcumin on experimental colitis-induced necroptosis of intestinal epithelial cells was investigated, and its molecular mechanism was further explored. We found that curcumin blocked necroptosis in a dose-dependent manner by inhibiting the phosphorylation of RIP3 and MLKL instead of RIP1 in HT-29 cells. Co-Immunoprecipitation assay showed that curcumin weakened the interaction between RIP1 and RIP3, possibly due to the direct binding of curcumin to RIP3 as suggested by drug affinity responsive target stability analysis. In a classical in vivo model of TNF-α and pan-caspase inhibitor-induced necroptosis in C57BL/6 mice, curcumin potently inhibited systemic inflammatory responses initiated by the necroptosis signaling pathway. Then, using a dextran sodium sulfate-induced colitis model in C57BL/6 mice, we found that curcumin inhibited the expression of p-RIP3 in the intestinal epithelium, reduced intestinal epithelial cells loss, improved the function of the intestinal tight junction barrier, and reduced local intestinal inflammation. Collectively, our findings suggest that curcumin is a potent targeted RIP3 inhibitor with anti-necroptotic and anti-inflammatory effects, maintains intestinal barrier function, and effectively alleviates colitis injury.

Disrupted White Matter Microstructure in Patients With Fibromyalgia Owing Predominantly to Psychological Factors: A Diffusion Tensor Imaging Study.

BACKGROUND: Neuroimaging investigations have already uncovered alterations to cerebral microstructural integrity in patients with fibromyalgia (FM). In the meantime, these patients commonly suffer from depression and anxiety. OBJECTIVE: In this study, microstructure changes within white matter were examined in patients with FM with consideration of concurrent physiological factors. STUDY DESIGN: A cross-sectional case-control study. SETTING: A university hospital. METHODS: Diffusion tensor imaging was performed on 20 patients with FM and 20 healthy controls. The 4 diffusional indices, namely, fractional anisotropy (FA), mean, radial, and axial diffusivity (MD, RD, AD) were calculated using tract-based spatial statistics. The relationships between the diffusional parameters and pain scales were also examined. RESULTS: The patients with FM exhibited enhanced FA, reduced MD, RD, and AD in numerous white matter tracts, including the corpus callosum, corona radiata, internal capsule, corticospinal tract, posterior thalamic radiation, cerebellar peduncle, sagittal stratum, and superior fronto-occipital fasciculus. When depression and anxiety were added as covariates, most between-group diffusional difference disappeared except for AD reduction in the corona radiate, internal capsule, and cerebellar peduncle (P < 0.05, threshold-free cluster enhancement corrected). The diffusion tensor imaging measures were not correlated with clinical variables. LIMITATION: A relatively small sample size. CONCLUSION: Our results demonstrate that disrupted white matter microstructure in patients with FM is mainly restricted to tracts associated with pain sensory processing and motor control, adjusting for psychosocial factors. A considerable degree of difference in white matter characteristics may be explained by the patients with FM group's greater level of psychological distress.

Astragaloside IV Protects Sepsis-induced Acute Kidney Injury by Attenuating Mitochondrial Dysfunction and Apoptosis in Renal Tubular Epithelial Cells.

BACKGROUND: Acute kidney injury (AKI) is closely linked to the pathogenesis of sepsis. Oxidative stress can affect the development of AKI by increasing damage to renal tubular epithelial cells. Astragaloside IV (AS-IV) is a natural saponin widly verified beneficial for ameliorating sepsis-induced kidney injury. However, the underlying mechanisms of AS-IV on relieving oxidative stress in renal tubular epithelial cells are yet to be established. PURPOSE: We aimed to investigate whether AS-IV could attenuate mitochondrialdysfunction and apoptosis in renal tubular epithelial cells and reveal its underlying mechanisms. METHODS: For the in vivo study, mice were divided into four groups (n=6): sham+saline, CLP+saline, CLP+ASIV- low dosage (5 mg/kg), CLP+AS-IV-high dosage (10 mg/kg), After 6 h or 24 h of treatment, the renal injuries were assessed based on related parameters of blood, protein and histopathological examination. Immunohistochemistry and ELISA were used to examine renal function. The molecular mechanism of AS-IV inhibited apoptosis and mitochondrial damage were monitored by flow cytometry and western blot analysis in HK-2 cells. RESULTS: We found that AS-IV ameliorates renal vacuolization, brush border loss, mitochondrial ultrastructure changes in sepsis-induced AKI, and the apoptosis and oxidative damage were greatly mitigated by AS-IV (10 mg/kg)-treated group. Abnormal changes in mitochondrial morphology and mitochondrial membrane potential were alleviated, and the expression of mitochondrial complex protein I (NDUFB8) and mitochondrial complex protein II (SDHB8) increased with (10 mg/kg)-treated group. Tubular epithelial cell apoptosis in AS-IV (20 µM)-treated cells was reduced by the Bax and cleaved caspase3 pathway. CONCLUSION: These studies demonstrated that AS-IV protects against sepsis-induced kidney tubular injury by alleviating oxidative stress, mitochondrial dysfunction possibly associated with the restored cleaved caspase3 pathway.

Cortical Abnormalities in Patients with Fibromyalgia: A Pilot Study of Surface-Based Morphometry Analysis.

BACKGROUND: Although neuroanatomical studies correlated to fibromyalgia (FM) are gaining increasing interest, the cortical morphology of patients are largely unknown, and data on cortical gyrification are scarce. The objective of the present study is to assess the cortical morphology in female patients with FM compared with healthy controls (HC) using surface-based morphometry (SBM) analysis of magnetic resonance imaging (MRI). METHODS: T1-MRIs and clinical data of 20 FM patients and 20 HC subjects were obtained from a public data set via OpenNeuro. For each subject, surface parameters including cortical thickness, local gyrification index (LGI), sulcal depth, and fractal dimensionality were estimated using SBM analysis. These data were compared between two groups controlled by age. The correlations between regional SBM parameters showing group differences and clinical profiles were analyzed. RESULTS: Compared with HC subjects, FM patients showed reduced cortical thickness in right primary motor cortex, lower LGI in right rostral anterior cingulate and higher sulcal depth in right precuneus (P < 0.05 cluster level family- wise error corrected). In FM patients, correlation analysis showed that the cortical thickness in right primary motor cortex were inversely correlated with scores of pain catastrophizing scale (r = -0.498, P = 0.030) and pain self-perception scale (r = -0.527, P = 0.020), and disease duration (r = -0.488, P = 0.034), respectively. CONCLUSIONS: Our findings provide evidence of neuroanatomical aberrations in FM patients, which may provide insight into the neuropathology of FM.

Anti-Apoptosis of Podocytes and Pro-Apoptosis of Mesangial Cells for Telmisartan in Alleviating Diabetic Kidney Injury.

Podocytes damage and mesangial cells expansion are two important pathological manifestations of glomerular injury in early diabetes. Telmisartan, as an angiotensin type 1 (AT1) receptor inhibitor, could improve advanced glycation end (AGE) products or angiotensin Ⅱ (Ang Ⅱ)-induced podocytes injury including detachment or apoptosis. In this current paper, we first confirmed the protective effect of telmisartan on early diabetic kidney injury in type 1 diabetic rats. Telmisartan reduced the loss of podocin and inhibited the expression of α-SMA, reflecting its protective effect on podocyte injury and mesangial proliferation, respectively. More interestingly we observed an opposite effect of telmisartan on the cell viability and apoptosis of podocytes and mesangial cells in a high-glucose environment in vitro. The anti-apoptotic effect of telmisartan on podocytes might be related to its inhibition of swiprosin-1 (a protein can mediate high glucose-induced podocyte apoptosis) expression. While telmisartan induced a high expression of PPARγ in mesangial cells, and GW9662 (a PPARγ antagonist) partially inhibited telmisartan-induced apoptosis and reduced viability of mesangial cells. In addition, high glucose-induced PKCß1/TGFß1 expression in mesangial cells could be blocked by telmisartan. These data provide a more precise cellular mechanism for revealing the protective effect of telmisartan in diabetic kidney injury.

A Response Surface Analysis of the Combination of Dexmedetomidine and Sufentanil for Attenuating the Haemodynamic Response to Endotracheal Intubation.

Purpose: Dexmedetomidine combined with opioids has been extensively used to blunt cardiovascular responses to endotracheal intubation. To determine their interaction, we aimed to develop a response surface model between dexmedetomidine and sufentanil. Methods: One hundred and twenty patients undergoing scheduled gynaecological surgery were recruited. According to a simulation of slice design, patients received different dose pairs of dexmedetomidine (0 to 1.1 µg/kg) and sufentanil (.1 to .5 µg/kg). The mean arterial blood pressure and heart rate of patients were recorded just before endotracheal intubation, immediately after intubation, and during the first 3 min after intubation. The primary outcomes were haemodynamic changes. The full dose-response relationship between dexmedetomidine and sufentanil was analysed using a logit model. Results: This response surface model revealed that the interaction between dexmedetomidine and sufentanil was additive. The dose pairs that could effectively attenuate the haemodynamic response to endotracheal intubation primarily ranged from .3 to .4 µg/kg and .5 to 1.1 µg/kg for sufentanil and dexmedetomidine, respectively. Conclusion: When used propofol as the main hypnotic drug during anaesthesia induction, dexmedetomidine could effectively reduce the requirement of sufentanil in an additive manner. However, it is not an effective drug for ablating the cardiovascular response to endotracheal intubation when used alone. The clinical trial registry. The trial registry name: Chinese Clinical Trial Registry. Registration number: ChiCTR1800015273. URL:http://www.chictr.org.cn.